Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
A nine amino acid domain is essential for mutant prion protein toxicity.
Westergard L, Turnbaugh JA, Harris DA.
???displayArticle.abstract???
Transgenic mice expressing prion protein (PrP) molecules with several different internal deletions display spontaneous neurodegenerative phenotypes that can be dose-dependently suppressed by coexpression of wild-type PrP. Each of these deletions, including the largest one (Δ32-134), retains 9 aa immediately following the signal peptide cleavage site (residues 23-31; KKRPKPGGW). These residues have been implicated in several biological functions of PrP, including endocytic trafficking and binding of glycosaminoglycans. We report here on our experiments to test the role of this domain in the toxicity of deleted forms of PrP. We find that transgenic mice expressing Δ23-134 PrP display no clinical symptoms or neuropathology, in contrast to mice expressing Δ32-134 PrP, suggesting that residues 23-31 are essential for the toxic phenotype. Using a newly developed cell culture assay, we narrow the essential region to amino acids 23-26, and we show that mutant PrP toxicity is not related to the role of the N-terminal residues in endocytosis or binding to endogenous glycosaminoglycans. However, we find that mutant PrP toxicity is potently inhibited by application of exogenous glycosaminoglycans, suggesting that the latter molecules block an essential interaction between the N terminus of PrP and a membrane-associated target site. Our results demonstrate that a short segment containing positively charged amino acids at the N terminus of PrP plays an essential role in mediating PrP-related neurotoxicity. This finding identifies a protein domain that may serve as a drug target for amelioration of prion neurotoxicity.
Aguzzi,
Mammalian prion biology: one century of evolving concepts.
2004, Pubmed
Aguzzi,
Mammalian prion biology: one century of evolving concepts.
2004,
Pubmed Ashok,
Selective processing and metabolism of disease-causing mutant prion proteins.
2009,
Pubmed Atarashi,
Deletion of N-terminal residues 23-88 from prion protein (PrP) abrogates the potential to rescue PrP-deficient mice from PrP-like protein/doppel-induced Neurodegeneration.
2003,
Pubmed Baeuerle,
Chlorate--a potent inhibitor of protein sulfation in intact cells.
1986,
Pubmed Baumann,
Lethal recessive myelin toxicity of prion protein lacking its central domain.
2007,
Pubmed Borchelt,
A vector for expressing foreign genes in the brains and hearts of transgenic mice.
1996,
Pubmed Brimacombe,
Characterization and polyanion-binding properties of purified recombinant prion protein.
1999,
Pubmed Büeler,
Normal development and behaviour of mice lacking the neuronal cell-surface PrP protein.
1992,
Pubmed Cardin,
Molecular modeling of protein-glycosaminoglycan interactions.
1989,
Pubmed Caughey,
Sulfated polyanion inhibition of scrapie-associated PrP accumulation in cultured cells.
1993,
Pubmed Chen,
Truncated forms of the human prion protein in normal brain and in prion diseases.
1995,
Pubmed Chen,
Interaction between human prion protein and amyloid-beta (Abeta) oligomers: role OF N-terminal residues.
2010,
Pubmed Chiesa,
Neurological illness in transgenic mice expressing a prion protein with an insertional mutation.
1998,
Pubmed Christensen,
A deleted prion protein that is neurotoxic in vivo is localized normally in cultured cells.
2009,
Pubmed Doh-ura,
Treatment of transmissible spongiform encephalopathy by intraventricular drug infusion in animal models.
2004,
Pubmed Drisaldi,
Genetic mapping of activity determinants within cellular prion proteins: N-terminal modules in PrPC offset pro-apoptotic activity of the Doppel helix B/B' region.
2004,
Pubmed Fischer,
Prion protein (PrP) with amino-proximal deletions restoring susceptibility of PrP knockout mice to scrapie.
1996,
Pubmed Gu,
Identification of cryptic nuclear localization signals in the prion protein.
2003,
Pubmed Hachiya,
Microtubules-associated intracellular localization of the NH2-terminal cellular prion protein fragment.
2004,
Pubmed Hachiya,
Anterograde and retrograde intracellular trafficking of fluorescent cellular prion protein.
2004,
Pubmed Harris,
New insights into prion structure and toxicity.
2006,
Pubmed Li,
Neonatal lethality in transgenic mice expressing prion protein with a deletion of residues 105-125.
2007,
Pubmed Mallucci,
Depleting neuronal PrP in prion infection prevents disease and reverses spongiosis.
2003,
Pubmed Mallucci,
Targeting cellular prion protein reverses early cognitive deficits and neurophysiological dysfunction in prion-infected mice.
2007,
Pubmed Mallucci,
Post-natal knockout of prion protein alters hippocampal CA1 properties, but does not result in neurodegeneration.
2002,
Pubmed Manson,
129/Ola mice carrying a null mutation in PrP that abolishes mRNA production are developmentally normal.
1994,
Pubmed Massignan,
A novel, drug-based, cellular assay for the activity of neurotoxic mutants of the prion protein.
2010,
Pubmed Nunziante,
Essential role of the prion protein N terminus in subcellular trafficking and half-life of cellular prion protein.
2003,
Pubmed
,
Xenbase Ostapchenko,
The polybasic N-terminal region of the prion protein controls the physical properties of both the cellular and fibrillar forms of PrP.
2008,
Pubmed Pan,
Cell-surface prion protein interacts with glycosaminoglycans.
2002,
Pubmed Parkin,
Cellular prion protein regulates beta-secretase cleavage of the Alzheimer's amyloid precursor protein.
2007,
Pubmed Pasupuleti,
Antimicrobial activity of human prion protein is mediated by its N-terminal region.
2009,
Pubmed Prusiner,
Prions.
1998,
Pubmed Shmerling,
Expression of amino-terminally truncated PrP in the mouse leading to ataxia and specific cerebellar lesions.
1998,
Pubmed Shyng,
The N-terminal domain of a glycolipid-anchored prion protein is essential for its endocytosis via clathrin-coated pits.
1995,
Pubmed Shyng,
A glycolipid-anchored prion protein is endocytosed via clathrin-coated pits.
1994,
Pubmed Shyng,
A prion protein cycles between the cell surface and an endocytic compartment in cultured neuroblastoma cells.
1993,
Pubmed Shyng,
Sulfated glycans stimulate endocytosis of the cellular isoform of the prion protein, PrPC, in cultured cells.
1995,
Pubmed Solforosi,
Toward molecular dissection of PrPC-PrPSc interactions.
2007,
Pubmed Solomon,
An N-terminal polybasic domain and cell surface localization are required for mutant prion protein toxicity.
2011,
Pubmed Solomon,
Prion neurotoxicity: insights from prion protein mutants.
2010,
Pubmed Solomon,
Neurotoxic mutants of the prion protein induce spontaneous ionic currents in cultured cells.
2010,
Pubmed Sunyach,
The mechanism of internalization of glycosylphosphatidylinositol-anchored prion protein.
2003,
Pubmed Supattapone,
Identification of two prion protein regions that modify scrapie incubation time.
2001,
Pubmed Taubner,
Structure of the flexible amino-terminal domain of prion protein bound to a sulfated glycan.
2010,
Pubmed Taylor,
Assigning functions to distinct regions of the N-terminus of the prion protein that are involved in its copper-stimulated, clathrin-dependent endocytosis.
2005,
Pubmed Taylor,
Glypican-1 mediates both prion protein lipid raft association and disease isoform formation.
2009,
Pubmed Wadia,
Pathologic prion protein infects cells by lipid-raft dependent macropinocytosis.
2008,
Pubmed Warner,
Identification of the heparan sulfate binding sites in the cellular prion protein.
2002,
Pubmed Yoshikawa,
Dominant-negative effects of the N-terminal half of prion protein on neurotoxicity of prion protein-like protein/doppel in mice.
2008,
Pubmed Zulianello,
Dominant-negative inhibition of prion formation diminished by deletion mutagenesis of the prion protein.
2000,
Pubmed
